We plan to continue our studies of gradually imposed, Adult-initiated Dietary Restriction (ADR) on spontaneous cancer and immunologic status in mice. Our recent findings show that mice subjected to ADR when 12-13 mo. old live longer, develop less lymphomas, and show less signs of immune system aging than do unrestricted controls. These diets supply similar intakes of protein, vitamins and salts to all mice while limiting calories for ADR mice (70% of control intake for first month of ADR, 55% thereafter). This project has 5 specific aims: i) Completion of A.CA/Sn studies: This strain develops pulmonary tumors and hepatomas. The study was delayed due to breeding problems which were overcome. The study is proceeding well (mice now 21 mo. old). Mice were underfed from weaning, 5 or 10 mo. of age or not at all. Survival and cancer incidence are being studied in most mice. Other mice are being studied for several age-sensitive immunologic parameters. ii) Studies on natural cell-mediated cytotoxicity (NCMC): We recently found that mice restricted since weaning show a lower basal natural killer (NK) cytolysis of the YAC-1 lymphoma but increased Poly I:C induced NK responses. We propose to continue these studies and extend them to ADR mice. Natural cytotoxic (NC) cells (which kill solid tumors) will also be studied. Restricted and control mice of several ages will be studied to determine NK and NC cell levels, kinetics of NK activation by Poly I:C and other interferon inducers, interferon production, response to interferon, surface antigen profile of splenocytes before and after Poly I:C injection, in vitro effect on NK of interleukin 2 (IL 2), and thymocyte regulation of NK activity. iii) Studies on interleukins: We recently found that mice restricted since weaning produce less IL 2 in response to Con A stimulation than controls. We plan on measuring IL 1 and IL 2 production by cells from ADR and control mice at diverse ages. iv) Effect of dietary retinoids or antioxidants on NCMC and T cell cytolysis: The impact of these substances added to diets of ADR and control mice will be tested. v) Spontaneous lymphoma studies: We plan to test the ability of restricted mice to withstand challenge with spontaneous syngeneic lymphomas. Also, T-cell and NK responses mounted against these lymphomas will be studied. The importance of the proposed work related to the development and immunologic understanding of a potent tactic of cancer inhibition.